International Omega-3 Learning and Education Consortium for Health and Medicine

Inflammation - an overview

Inflammation is a normal defense mechanism that protects the host from infection and other insults; it initiates pathogen killing as well as tissue repair processes and helps to restore homeostasis at infected or damaged sites ¹. It is typified by redness, swelling, heat, pain and loss of function, and involves interactions amongst many cell types and the production of, and responses to, a number of chemical mediators. Where an inflammatory response does occur, it is normally well regulated in order that it does not cause excessive damage to the host, is self-limiting and resolves rapidly. This self-regulation involves the activation of negative feedback mechanisms such as the secretion of anti-inflammatory cytokines, inhibition of pro-inflammatory signaling cascades, shedding of receptors for inflammatory mediators, and activation of regulatory cells. As such, when controlled properly, regulated inflammatory responses are essential to remain healthy and maintain homeostasis. Pathological inflammation involves a loss of tolerance and/or of regulatory processes. Where this becomes excessive, irreparable damage to host tissues and disease can occur. A number of diseases and conditions are now recognized to involve inflammation or to have an inflammatory component. These include the "classic" inflammatory diseases like rheumatoid arthritis, ulcerative colitis, Crohn's Disease, and asthma. However, other common lifestyle-related diseases such as atherosclerosis and obesity are now known to have an important inflammatory component, as do degenerative diseases of aging like Alzheimer's Disease.

Arachidonic acid-derived eicosanoids and inflammation

The key link between fatty acids and inflammation is that the eicosanoid family of inflammatory mediators is generated from 20 carbon polyunsaturated fatty acids (PUFA) ^2,3. Because inflammatory cells typically contain a high proportion of the omega-6 PUFA arachidonic acid (AA) and low proportions of other 20-carbon PUFA, AA is usually the major substrate for eicosanoid synthesis. Eicosanoids include prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and other oxidized derivatives. These are generated from arachidonic acid by metabolic processes involving cyclooxygenase and lipoxygenase enzymes. Eicosanoids are involved in modulating the intensity and duration of inflammatory responses and have cell- and stimulus-specific sources. The cyclooxygenase pathway is important in the pathophysiology of many inflammatory diseases. AA metabolism is a long recognized target for non-steroidal anti-inflammatory drugs (NSAIDs) that act to inhibit cyclooxygenase activity in inflammatory conditions. Although these considerations have given rise to the view that AA-derived mediators are, by definition, pro-inflammatory, this is an oversimplification because some of these mediators like prostaglandin E₂ have both pro- and anti-inflammatory roles while others, like lipoxin, have only anti-inflammatory effects ⁴.

Marine omega-3 PUFA and inflammatory eicosanoid production

Increased consumption of the marine omega-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) results in increased proportions of these fatty acids in inflammatory cell phospholipids ³. The incorporation of EPA and DHA into human inflammatory cells occurs in a dose-response fashion and is partly at the expense of AA ³. EPA and DHA also inhibit AA metabolism ^2,3. The functional outcome of these effects is to decrease production of eicosanoid mediators from AA. The reduction in generation of these eicosanoids has led to the idea that marine omega-3 PUFA are anti-inflammatory.

EPA is also able to act as a substrate for both cyclooxygenase and 5-lipoxygenase enzymes giving rise to eicosanoids with a slightly different structure to those formed from AA. The significance of this is that the mediators formed from EPA are frequently less potent than those formed from arachidonic acid ^2,4.

Marine omega-3 PUFA and resolvins

Recent studies have identified novel families of mediators formed from EPA and DHA, termed E-series and D-series resolvins, respectively ⁵. These mediators are formed by metabolic pathways involving the activity of cyclooxygenase and lipoxygenase enzymes acting sequentially, often in more than one cell type with transfer of metabolites between those cells. Resolvins exert potent anti-inflammatory and inflammation resolving actions that have been investigated in numerous cell culture and animal models, but with little data from the human setting. The identification of resolvins is an exciting new area of research in omega-3 fatty acids and inflammation, and the implications to a variety of conditions may be of great importance. These mediators may explain many of the anti-inflammatory actions of omega-3 fatty acids that have been described.

Marine omega-3 PUFA and peptide mediators of inflammation

Cell culture and animal studies demonstrate that EPA and DHA can inhibit the production of inflammatory cytokines like tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and IL-8 by inflammatory cells ². These cytokines are peptide mediators of inflammation that induce many of the cellular and whole body components of inflammation. However, human studies are less clear on this effect of marine omega-3 PUFA; some studies have replicated the effect seen in animal models while others have not ^6,7. This may be, in part, related to the amount of omega-3 PUFA consumed (higher intakes are more likely to cause an effect) but there appear to be other factors involved too. One of these could be the genetic makeup of the individuals concerned ⁷.

Do marine omega-3 PUFA work as anti-inflammatory agents in the clinic?

The recognition that the marine omega-3 PUFA have anti-inflammatory actions has led to the idea that supplementation of the diet of patients with inflammatory diseases may be of clinical benefit to those patients. Supplementation trials (usually with fish oils) have been conducted in a range of such diseases. The best explored have been rheumatoid arthritis, inflammatory bowel diseases (Crohn's disease and ulcerative colitis) and asthma, but there are trials in many other inflammatory diseases as well ^2,8,9.

Marine omega-3 PUFA have anti-inflammatory effects in patients with rheumatoid arthritis ⁸. Many trials with fish oils have been conducted in this condition. Almost all of these trials show a benefit from fish oil, such as reduced duration of morning stiffness, reduced number of tender or swollen joints, reduced joint pain, reduced time to fatigue, increased grip strength and decreased use of non-steroidal anti-inflammatory drugs. It is important to note that very high doses of marine omega-3 fatty acids have been used in most of these studies. Nevertheless, at these intakes, the evidence that marine omega-3 PUFA are effective in rheumatoid arthritis is convincing.

Marine omega-3 PUFA also have anti-inflammatory effects in patients with inflammatory bowel diseases, and again, many trials with fish oil have been conducted in these conditions ⁹. However, in contrast to the trials in rheumatoid arthritis, the evidence of clinical benefit is less obvious; even though, once again, quite high intakes have been used. This is a condition in which further trials are needed.

The anti-inflammatory effects of marine omega-3 PUFA were also studied in adults and children with asthma ¹⁰. However, studies in adults have failed to show a therapeutic benefit of marine omega-3 PUFA in adults with asthma ¹⁰. In children, there may be a prophylactic benefit on the incidence of allergic asthma when mothers were provided with adequate omega-3 fatty acids in the diet ¹¹. However, few studies have been conducted in children, and this is an area where more studies are needed.

Conclusions

Eicosanoids produced from AA are involved in inflammatory processes and are implicated in inflammatory conditions and diseases, symptoms of which may be treated by eicosanoid synthesis inhibitors. At sufficiently high intakes in humans, marine omega-3 PUFA decrease the production of inflammatory lipid and peptide mediators (eicosanoids, cytokines). They act in part by replacing AA as an eicosanoid substrate and inhibiting AA metabolism. Marine omega-3 PUFA also give rise to potent anti-inflammatory mediators (resolvins). Thus, marine omega-3 PUFA at sufficiently high intakes are potentially useful anti-inflammatory agents and may be of therapeutic value in a variety of acute and chronic inflammatory settings. Evidence of the clinical efficacy of marine n-3 PUFA is strong in some settings (e.g. in rheumatoid arthritis) but is weak in others (e.g. in inflammatory bowel diseases and asthma). Moreover, better designed and larger trials are required in most inflammatory diseases to assess the therapeutic potential of marine omega-3 PUFA in these, and other, inflammatory conditions. It is possible that part of the protective and therapeutic effect of marine omega-3 PUFA in other conditions like cardiovascular diseases involves their anti-inflammatory actions.

References